Severe viral infections and bacterial sepsis are associated with a high mortality rate and limited treatment options. Current therapeutic approaches that target both thrombotic and thrombolytic pathways for the treatment of lethal sepsis result in a 6 to 19% reduction in death. And, although treatment approaches targeting inflammatory pathways have shown some success in clinical trials, a therapeutic approach that can affect innate immune responses through inactivation of serine proteases with minimal coagulopathic and hemorrhagic changes can provide a new treatment strategy for lethal viral infections and sepsis.